Sulfurenic acid and derivatives thereof



United States Patent 0 3,271,390 SULFURENIC ACID AND DERIVATIVES THEREOF Josef Fried, Princeton, N.J., assignor, by mesne assign- 5 ments, to E. R. qnibb & Sons Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed fiept. 13, 1963, Ser. No. 308,677

20 Claims. (Cl. 260-2395) This invention relates to and has as its object the pro- 10 vision of new physiologically active steroids, processes for their preparation and novel intermediates useful in said preparation.

The final products of this invention may be reprewherein R is hydrogen; each R is selected from the group consisting of hydroxy and acyloxy; and together R and R is oXo(O:); Y is acyl; and together R and CY is oXo(O=); each R is selected from the group consisting of hydrogen and hydroxy; and together R and R" is oxo(0=); R is selected from the group consisting of hydroXy, acyloXy and alkanoyloxy; and together R and R is oXo(O=); and Z is selected from the group consisting of hydrogen, hydroxy, halogen (e.g., chloro, fluoro, bromo, iodo) and acyloxy.

The preferred acyl and acyloxy radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric and tert-pentanoic acid), the lower alkenoic acids, the monocyclic aryl carboXylic acids (e.g., benzoic and toluic acid), the monocyclic aryl lower alkanoic acids (e.g., phenacetic and fl-phenylpropionic acid), the cycloalkane carboxylic acids and the cycloalkene carboxylic acids.

The alkanoyl groups preferably employed in the practioe of this invention may be either straight or branched chain and are those having less than ten carbon atoms, for example, hexanoyl, pentanoyl, heptanoyl, lower alkylalkanoyl, such as methyl-hexanoyl, or di-lower alkyl alkanoyl, such as dimethyl-hexanoyl.

[In this application and in the appended claims, whenever in the formulae set forth herein line (I) is employed in the linkage of atoms, it is meant to denote that the connected atom may be either in the alpha or beta position, as is determined in the respective compounds involved] Those final pregnane and A-nor pregnane products of this invention which are unsubstituted in the 21-position (i.e., Z is hydrogen or halogen) are physiologically active compounds which possess progestational activity and thus can be employed instead of progesterone, for example, in

the treatment of habitual abortion for which purpose they can be administered in the same manner as progesterone, for example, the dosage being adjusted for the relative potency of the particular steroid. Those final products of this invention which are oxygenated in the 21-position (i.e., Z is hydroxy or acyloxy) are physiologically active compounds which possess mineralocorticoid activity and thus can be employed instead of desoxycorticosterone, for example, in the treatment of Addisons disease, for which they can be administered in the same manner as desoxycorticosterone, for example, the dosage being adjusted for the relative potency of the particular steroid.

In addition, it has been found that the A-nor compounds of this invention are physiologically active steroids which possess antiandrogenic activity, i.e., they inhibit the action of androgens, and they can be used in the treatment of such conditions as hyperandrogenic acne. The compounds may be formulated for such administration, the concentration and/or dosage being based on the activity of the particular compound and the requirements of the patient.

The androstane final products of this invention are physiologically active steroids which possess proteinanabolic activity and which may be used in place of such known protein-anabolic steroids as 17-ethyl-19-nortestosterone in the treatment of post-operative shock and other conditions where tissue degeneration has occurred. Administration of the products of this invention may be accomplished either perorally or parenterally, in the same manner as 17-ethyl-19-nortestosterone, for example, the dosage and/or concentration being adjusted for the relative potency of the particular steroid. In addition, compounds of this invention are physiologically active steroids which possess androgenic activity and may be used in A Sulfurenic acid II IIa, YZCHBCO; R:CH

place of such known androgenically active steroids as testosterone in the treatment of enuchoidism being formulated for such administration in the same manner and/or dosage as testosterone.

The final products of this invention may be prepared by the processesses of this invention beginning with the novel starting material employable in the practice thereof.

To prepare the starting material which may be employed in this invention, a new compound, hereinafter referred to as sulfurenic acid, having the structural formula A, is first prepared. This compound may be prepared by first following the procedures set forth by Gascoigne, et al., Journal of the Chemical Society, (1951), pp. 2346-235 2. Generally, the procedure set forth teaches that a fungus, Polyprous sulfureus may be grown on a modified Williams-Saunders medium (Biochem. J., 1934, 28, 1887) with glucose (100 g. per liter) in place of sucrose and glycine (2 g. per liter) in place of asparagine. The Washed mycelium is then dried, milled to a fine powder, and extracted in a Soxhlet, first with light petroleum (B.P. 4060 C.) to remove fat and then exhaustively with ether or chloroform, preferably the latter. The chloroform extract thus obtained is then fractionated, the higher melting eburicoic acid fraction removed by crystallization and a lower melting fraction, rich in sulfurenic acid obtained. This sulfurenic acid fraction may then be purified by conversion into the mixture of methyl esters and crystallized from methanol from which methyl sulfurenate crystallizes preferentially. The latter is one of the starting materials for the products of this invention. The preparation of these derivatives may be represented by the following equations wherein R, R and R" may be hydrogen, alkyl, acyl or alkylene and Y0 may be hydroxy, acyloxy or oxo(0=):

CH1 ll Initiallly, sulfurenic acid (Compound A) derived from the aforementioned fermentation process is alkylated as by treatment with an alkylating agent (e.g., ethereal diazomethane) to yield the sulfurenic acid alkyl ester Compound Ia). Treatment of the sulfurenic acid alkyl ester (Compound Ia), with an acylating agent, e.g., an acid anhydride or acyl halide, for example acetic anhydride or benzoyl chloride in the presence of a nitrogen base (e.g., pyridine) yields the alkyl 3,15-diacyl sulfurenate (Compounds Ic), which are new compounds of this invention.

The diacyl sulfurenate (Compounds Ic) may then be hydrolyzed to the diacyl sulfurenic acid (Compounds lb) which are also new compounds of this invention by treatment with a nucleaphilic reagent, for example, lithium iodide in a base, such as collidine.

To obtain the 24(28) dihydro derivatives of sulfurenic acid, alkyl sulfurenate (Compound Ia) is first reduced as by treatment with palladium on charcoal, to yield the alkyl dihydrosulfurenate (Compounds Id), which are also new compounds of this invention. Compound Id may then be acylated as by treatment with an acylating agent, such as an acid anhydride or acyl halide in the presence of a base to yield the alkyl diacyl dihydrosulfurenate (Compounds e), which are also new compounds of this invention.

The 3,15-diketo derivatives of alkylsulfurenate (Compounds If) may be prepared by oxidizing the alkyl sulfurenate (Compounds Ia) by treatment with chromium trioxide in an acid medium, to yield other new starting materials of this invention.

The -keto derivatives of this invention (Compounds III) which are also new starting materials may be prepared by first reducing the diketo sulfurenate (Compounds If) as by treatment with potassium borohydride, to yield the 15-keto eburicoates (Compounds IIIa), which are also new compounds of this invention. Compounds IIIa may then be acylated to yield the 3-acyl derivative of 15-keto eburicoate (Compounds HIb) which are also new compounds of this invention. Compounds IIIa may also be reduced as by treatment with palladium on barium sulfate to obtain the 24(28) dihydro derivatives of IS-keto eburicoate (Compounds IIIc) which are also new starting materials of this invention.

The 24(28)-dihydro derivatives of IS-lreto ehuricoate (Compounds 1110) may then be subjected to a retropinacol rearrangement with phosphorus pentachloride to yield the 15-keto-A-nor-A -derivatives of alkyl sulfurenate (Compounds IV) which are also new starting compounds of this invention.

Additional starting materials may be obtained by treating the alkyl diacyl dehydrosulfurenate (Compounds Ie) with an oxidizing agent, such as chromium trioxide, to yield the diacyl 7,11 diketodehydroeburicoate (Compounds II) which are also new compounds of this invention.

The preparation of the new starting material may be illustrated by the following examples (all temperatures being in degrees wntigrade) EXAMPLE AA Sulfurenic acid methyl ester (Ia).-In fractionating the triterpene acids from Polyporus sulfureus, as described by Gascoigne et al. (J. Chem. Soc. [195-1] 2346 et seq.) there is obtained from the chloroform extract (employing chloroform in place of the ether of Gascoigne et al.) of the myceliurn after removal of the bulk of the eburicoic acid by crystallization a lower melting fraction (M.P. 255260) which is rich in sulfurenic acid. Ten grams of this material is suspended in methanol and an ethereal solution of diazomethane is added until methylation is complete. The solution is filtered from a small amount of insoluble residue and the solvents are evaporated in vacuo. The residual gum is taken up in rnet hanolch-loroform which results in the crystallization of 4.8 grams of practically pure sulfurenic acid methyl ester (Ia), melting at 1 192. Recrystallization from acetone gives the pure compound without change in melting point [04 +66 (c., 0.42 in chloroform):

2.83, 3.01, 5.84, 6.08, and 11.27

Analysis.--Calcd for C I-1 0 (507.3): C, 76.75; H, 10.47; OMe, 6.02. Found (after drying at 140 for tour hours): C, 76.61; H, 10.67; OMe, 5.73.

EXAMPLE BB Methyl 3,15-diacetyl sulfurenate (Ic).-One hundred mg. of methyl sulfurenate (Ia) is acetylated with 0.5 ml. of acetic anhydride for 20 hours at room temperature. After removal of the reagents in vacuo, the crude crystalline material is recrystallized from methanol. The resulting diacetate (1c) has the following properties: M.P. 138140; [M +67 (c., 0.41 in chloroform):

Analysis.-Calcd for C i-1 0 (584.81): C, 73.93; H, 9.65. Found: C, 73.61; H, 10.00; C, 74.03; H, 9.59; C, 74.16; H, 9.61.

EXAMPLE CC Diacetyl sulfurenic acid (Ib).-A solution of 250 mg. (0.5 mm.) of methyl sulfurenate (Ia) and 435 mg. of dried lithium iodide (3.3 mm.) in 10 ml. of anhydrous collidine is refluxed under helium for 18 hours. The reaction mixture is then poured onto ice and 2 N hydrochloric acid and the resulting suspension. extracted with methyl isobutyl ketone. The methyl isobutyl ketone extract is evaporated to dryness in vacuo, and the residue (153 mg.) is acetylated with 4 ml. of anhydrous pyridine and 2 ml. of acetic anhydride for 18 hours at room temperature. After removal of the reagents in vacuo, the mixture is distributed between dilute sulfuric acid and chloroform and the cholorform extract washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting residue mg.) is taken up in hexane, a small amount of residual material removed by centrifugation and the hexane solution evaporated to dryness. The residue crystallizes readily from methanol furnishining 71 mg. of diacetylsulfurenic acid (Ib) possessing the following properties: M.P. 234235; [54 +58 (c., 1.00 in chloroform):

hfii; 5.76, 5.87, 6.08, 8.04 and 1128p.

Analysis.Calcd for C H O C, 73.65; H, 9.54. Found: C, 73.76; H, 9.43.

EXAMPLE DD Sulfurenic acid.A suspension of 30 mg. of diacetyl sulfurenic acid (Eb) in 3 ml. of 0.7 N metbanol-KOH is stirred at room temperature for 20 hours under a blanket of helium. The resulting methanol is acidified to pH 2 with 4 N sulfuric acid and the mixture extracted with large volumes of hot methyl isobu-tyl ketone. The methyl isobutyl ketone extract is washed with Water and evaporated to dryness in vacuo. The resulting residue on crystallization from acetone furnishes 13 mg. of pure sulfurenic acid (A) M.P. 252-254; [M +42 (c., 0.51 in anhydrous pyridine).

Analysis.Calcd for C H O (486.71): C, 76.50; H, 10.36. Found (after drying at 135 for 2 /2 hours): C, 76.73; H, 10.18.

EXAMPLE EE Sulfllrenic acid (A).Into :a solution. of 1 g. of methyl sulfurenate (Ia) in 50 ml. of freshly distilled tetr ahydrofuran is passed ammonia gas with cooling until a total of 100 ml. has condensed. The methyl sulfurenate precipitates out and is present as a fine suspension. Small pieces of lithium are added with stirring and the flask removed from the cooling bath. The addition of lithium is continued until there is a persistent blue color and the ammonia is permitted to evaporate. A small amount of methanol is then added to dissolve the residual lithium. The mixture is acidified to pH 2 with dilute sulfuric acid and extracted with methyl isobutyl ketone. T he resulting methyl isobutyl lcetone extract is extracted with 1 N aqueous sodium hydroxide until all the acid has been removed from the methyl isobutyl ketone extract. The aqueous extracts are washed once with methyl isobutyl ketone and acidified with 2 N sulfuric acid to pH 2. The precipated acids are extracted again with hot methyl isobutyl ketone, the methyl isobutyl ketone extracts washed with Water and evaporated to dryness in vacuo. Ihe resulting residue (485 mg.) which consists essentially of the very insoluble sulfurenic acid is recrystallized from tetrahydrofuran-acetone and yields a total of 200 mg. of pure sulfurenic acid (A), identical in every respect with the acid prepared by the procedure of Example DD.

EXAMPLE FF Methyl dihydrosulfurenate (Id) .To a prereduced suspension of 1.5 g. of 10% palladium on charcoal in 40 ml. of ethyl acetate is added a solution of 1.5 g. of methyl sulfurenate (Ia) in 100 ml. of ethyl acetate and the resulting mixture agitated in the presence of hydrogen until uptake is complete which requires a total of two hours and thirty minutes. Total uptake-95 ml. of hydrogen. Calcd for 1 mole: 75 ml. The catalyst is removed by filtration and the solution evaporated to dryness in vacuo. The residue on recrystallization from methanol furnishes 1.27 g. of methyl dihydrosulfurenate (Id) possessing the following properties: M.P. 200-202; x] +65 (c., 0.46 in chloroform);

Analysis.Calcd for C l-1 0 (502.75): C, 76.44; H, 10.83. Found: C, 76.32; H, 10.87.

Evaporation of the lowest mother liquor furnishes an isomer of methyl dihydrosulfurenate (112 mg), isomeric at C24 with the compound described above, as shown by acetylation to be described in the following examples.

EXAMPLE GG Methyl diacetyl dihydrosulfurenate (Ie).Five hundred mg. of methyl dihydrosulfurenate (Id) is acetylated with 5 ml. of pyridine and 10 ml. of acetic anhydride for a total of 24 hours. Removal of the reagents furnishes a residue which is recrystallized from methanol. Recrystallization from that same solvent furnishes pure methyl diacetyl dihydrosulfurenate (Ie) of the following properties: M.P. l40-142; [ch +67 (c., 0.42 in chloroform) Analysis.-Calcd for C H O (586.82): C, 73.68; H, 9.96. Found (after drying at 110 for four hours): C, 74.80; H, 9.91.

The lowest mother liquor material obtained in the catalytic hydrogenation (Example FF) of methyl sulfurenate (112 mg.) is acetylated with 1 ml. of pyridine and 2 ml. of acetic anhydride for 24 hours. The reagents are removed in vacuo and the residue dissolved in benzene and filtered through a small amount of neutral alumina (activity I). Evaporation of the benzene gives 105 mg. of crude diacetate which is further purified by preparative thin layer chromatography. The pure 24-isomer of methyl diacetyldihydrosulfurenate has the following properties: 153-1556; +55 (c., 0.48 in chloroform) AnaIysis.-Calcd for C H O (586.2): C, 73.68; H, 9.96. Found: C, 73.76; H, 10.06.

EXAMPLE HH Methyl-A -eburicadiens-3,15-di0ne-21-0ate (If) To a solution of 1 gram of methyl sulfurenate (Ia) in 25 ml. of acetone is added at room temperature with stirring 1.9 ml. of Jones reagent (200 mg. of chromium trioxide and 320 mg. of sulfuric acid in 1 ml. of water), dropwise at room temperature. After 25 minutes at room temperature methanol is added dropwise to reduce the excess chromium trioxide. Water is then added and the bulk of the acetone is evaporated in vacuo. The residue is extracted with chloroform, the chloroform extract washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The crude residue upon recrystallization from methanol furnishes the pure methyl-A -eburicadiene-3,15-dione 21 oate (If) (743 mg.) possessing the following properties: M.P. 141- 143"; [04],; +735 (c., 0.40 in chloroform):

Analysis.Calcd for C H O (496.70): C, 77.37; H, 9.74. Found: C, 77.23; H, 9.65.

EXAMPLE I] Methyl 15-ket0-eburic0ate (IIIa).-To a solution of mg. of potassium borohydride in 30 ml. of water and 30 ml. of dioxane is added at room temperature with stirring a solution of 300 mg. of methyl-11 eburicadiene-3,1S-dione-Zl-oate (If) in 30 ml. of dioxane. The reaction is allowed to proceed for 45 minutes at room temperature, after which time excess potassium borohydried is destroyed by the addition of glacial acetic acid. The mixture is taken up in chloroform, the chloroformdioxane phase washed with water, and evaporated to dryness in vacuo. Crystallization of the residue from methanol furnishes 268 mg. of material melting at 130- 132 and in addition 120 mg. melting at 118-120. The analytically pure methyl 15-keto-eburicoate (Illa) has the following properties: M.P. 130-132 (solvated); [04 +71 (0., 0.47 in chloroform):

$ 5,112.92, 5.77, 6.10 and 11.28;:

Analysis.Calcd for C H O (498.72): C, 77.06; H, 10.11. Found: C, 76.66; H, 9.99.

EXAMPLE KK KB AMI);-

5.77, 6.10, 8.08 and 11.15,.

Analysis.-Calcd for (3 11 0 (528.75 1 c, 74.96; H, 9.91. Found: c, 75.07; H, 9.76.

EXAMPLE LL Methyl 15-ket0-dihydr0buric0ate (IIIf).To a prereduced suspension of 80 mg. of 5% palladium on barium sulfate in 20 ml. of ethyl acetate is added a solution of 200 mg. of methyl 15-keto-eburicoate (IIIa) in 20 ml. of ethyl acetate. The reduction is continued until hydrogen uptake is complete (11.0 ml.). Theory for 1 mole ml. The catalyst is removed by filtration and the filtrate evaporated to dryness in vacuo. The residual material after recrystallization from methanol melts at 144150 and is strongly solvated. Recrystallization from acetonitrile gives methyl 1S-keto-dihydroeburicoate (IIIc) that melts at 144-148; [a] +62 (c., 1.00 in chloroform).

Analysis.Ca1cd for C H O (500.73): C, 76.5; H, 10.47. Found: (after drying at 100 for four hours) C, 76.70; H, 10.41.

EXAMPLE MM Wolfj-Kishner reduction of methylacetyl-IS-ketO-eburicoate (lllb) to methyl eburicoata-Ten ml. of 95% hydrazine hydrate and 10 grams of sodium hydroxide pellets is refluxed for three hours and then a sufficient amount of the dried hydrazine is distilled into 10 ml. of redistilled diethylene glycol, in which 200 mg. of sodium has been dissolved and which has been preheated to 180, to insure reflux of the mixture at 180. The mixture is then cooled to room temperature and 100 mg. of vacuum-dried (100) methyl acetyl--keto-eburicoate (IIIb) is added. The resulting solution is then refluxed for 18 hours at 180, after which time hydrazine is distilled off to secure reflux of the solution at 210 (measured in the liquid) for 24 hours. The cooled mixture is acidified with 4 N sulfuric acid and taken up in methyl isobutyl ketone and water. The aqueous phase is extracted several times with methyl isobutyl ketone and the combined methyl isobutyl ketone extracts evaporated to dryness in vacuo. The total residue (95 mg.) is taken up in 2 ml. of methanol and remethylated with ethereal diazomethane for minutes. After removal of the solvents in vacuo, the crystalline residue is recrystallized from methanol, furnishing 47 mg. of material melting at 117-125 This material is further purified by preparative thin layer chromatography on activity V alumina using chloroform-hexane (1:1) as the liquid phase. The zone possessing an R of approximately 0.3 (the first zone from the origin) is eluted with ethyl acetate and furnished 13 mg. of crystalline material. This material on recrystallization from methanol gives pure methyl eburicoate, melting at 114-115. Identity is confirmed by acetylation, which furnishes pure methyl acetyl eburicoate melting at 151-153, and Which gives no depression when mixed with an authentic sample, and whose infrared spectrum is identical with that of such a sample as obtained in copending application Serial No. 183,014, filed March 28, 1962, by Josef Fried et al.

EXAMPLE NN Methyl diacetyl-7,1I-diketodihydroeburi'coate (II) .-To a solution of mg. of methyl diacetyl-dihydrosulfurenate (Ie) in 5 ml. of glacial acetic acid is added at 70 dropwise with stirring a solution of mg. of chromium trioxide in a few drops of water and 4 ml. of glacial acetic acid. Addition of the oxidizing agent is complete after 40 minutes and the reaction is allowed to proceed for a total of one hour at 7080. The reaction. mixture is then cooled and the excess oxidant reduced by the addition by a few drops of methanol. The mixture is concentrated to small volume and taken up in isobutyl ketone and water. The organic phase is washed with Water, dried over sodium sulfate and evaporated to dryness in vacuo. The crude residue weighing 237 mg. is dissolved in 5 ml. of hexane and chromatographed on 4.7 grams of neutral alumina, activity I. Elution of the column with 200 ml. of hexane leaves a small amount of amorphous material. Subsequent elution with benzene-hexane (1:1) (200 ml.) followed by benzene alone (250 ml.) gives the desired methyl diacetyl-7,11-diketo dihydroeburicoate (II) which after crystallization from methanol has the following properties: M.P. 181; [a] +79 (c., 0.41 in chloroform):

Analysis.Calcd for C H O (614.79): C, 70.33; H, 8.55. Found: C, 70.38; H, 8.83.

EXAMPLE OO Methyl 1 4-mezhyl-3-is0 pro pylideneA -A -n0r-5 a-ergostene-15-0ne-21-0ate (lV).Through a solution of 30 mg. of methyl 1S-keto-dihydroe-buricoate (IIIc) in 10 ml. of dry toluene is passed with stirring at 0 a vigorous stream of helium gas. To this mixture is added 30 mg. of phosphorus pentachloride in the dark. After a total reaction time in the dark of six minutes, saturated sodium bicar bonate is added and the mixture stirred for an additional five minutes. The layers are then separated and the toluene extract washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residual material material is recrystallized from acetonitrile and furnishes the methyl 14-methyl-3-isopropylidene-A -A-nor-5a-ergostent-15-one-21-oate (IV) (19 mg.) possessing the following properties: M.P. 141-145":

These novel starting materials may then be employed according to the processes of this invention to yield the new final products of this invention. The starting materials of this invention may be processed in accordance with the teachings and disclosures set forth in copending applications Serial No. 183,014, filed March 28, 1962, in the names of Josef Fried and David Walter Rosenthal, now Pat. No. 3,153,038 which is a continuation-in-part application of Serial No. 132,310, filed August 18, 1961, and now abandoned; application Serial No. 198,425, filed May 29, 1962, in the names of Josef Fried and Gerald Krakower; now US. 3,169,957 and application Serial No. 212,154, filed July 24, 1962, in the name of Josef Fried now Pat. No. 3,170,919. The processes of this invention, employing the novel starting materials thereof may be rep- KBr. Max.

resented by the following equations, wherein YO, Y, R, R' and R are as hereinbefore defined, and A is lower alkyl:

CH OH:

noC g Sulfurenic acid RzCHaCO; R:H

R CHsCO; R CHa R CHaCO YO O:

Compounds C are then lactonized by treatment with an acid anhydride and a salt of a strong base and a weak acid, such as sodium acetate in acetic anhydride, to yield a mixture of the a-lactone (Compounds D) and fl-lactone (Compounds E) of the corresponding 3,15-diesters of 3ft, 15a-dihydpoxy-24-keto-A -lanostene-2l-oic acid. These lactones are new compounds of this invention. The reaction is preferably carried out at an elevated temperature, such as the reflux temperature of the organic solvent employed and the two lactones are separated chromatographically. However, since both the u-lactone and filactone give the same product in the next step of the process of this invention, such separation is not necessary and a mixture of the lactones may be used directly.

, Compounds D and E are then dehydrogenated, as by treatment with palladium on charcoal at an elevated temperature, to yield the corresponding 3,15-diester of 36,15a, 24-trihydroxy-A -lanostadiene-2l-oic acid lact-one (Compounds P), which are new compounds of this invention. If desired, the ester can then be saponified in the usual manner, as by treatment with a base such as potassium hydroxide to yield the corresponding free 3d, lfia-dihydroxy derivative, and the free 3,15-dihydroxy compound oxidized to the corresponding 3,15-diketo derivative in the usual manner, as by treatment with chromium trioxide.

Compounds F can then be isomerized to the corresponding 3B,15ot,24 trihydroxy A' lanostadiene-Zl-oic acid lactone derivative (Compounds G), which are new compounds of this invention, by treatment with hydrogen chloride in a solvent (e.g., glacial acetic acid).

Compounds F and G are then converted to the final 2l-oxygenated pregnene derivatives of this invention by the same series of steps. If a Compound F is employed the final products and all intermediates contain a doublebond in the 8,9-position. If a Compound G is employed, the final products and all intermediates contain a double-bond in the 7,8-position.

In the first step of this process, Compounds F and G are reduced by treatment with lithium aluminum hydride to yield the corresponding 3fl,15a,2l-trihydroxy- M -lanostatriene (Compounds H) and 35,15a, 2l-trihydroXy-A -lanostatri'ene (Compounds J) derivaives, respectively. These compounds can be converted to their 21-ester (or 3,15,21-triester, if a free 3,15- dihydroxy compound is initially produced) derivatives by the usual acylation procedure. The preferred acylating agents are the acyl chlorides and acid anhydrides of the hydrocarbon carboxylic acids of less than twelve carbon atoms mentioned hereinbefore. All Compounds H and J are new compounds of this invention.

Compounds H and J are then oxidized, as by treat- 16 ment with ozone and reduction of the ozonide formed,

yield 3 8, 1 511,2 1 -trihydroxy-4,4, 14u-trimethyl-A' -5apregnene-ZO-one (Compounds L), respectively, or monodior triester of each of these depending on the degree of esterification of the starting material. Moreover, if a triester is initially formed, it can be selectively saponifi'ed to the 3,15-diester by treatment with potassium carbonate and if a trihydroxy compound is initially formed, it can be selectively esterified to the 2l-monoester by treatment with the desired acid anhydride in pyridine. Thus, all combinations of Compounds K and L, containing two or three free hydroxyl groups, a 3-monoester group, a 21-monoester group, a 3,2l-diester group, a 3,15-diester group or a 3,15,2l-triester group can be obtained. Compounds K and L are new compounds of this invention.

Compounds K and L, containing free 3,15-dihydroxy groups, can then be oxidized in the usual manner, as by treatment with chromium trioxide, to yield the final products of this invention, which contain either a 21- hydroxy group or a 2l-acyloxy group (Compounds M and N).

If a ZI-unsubstituted compound is desired (Compounds S and T), a Compound K, L, M or N, containing a free 21-hydroxy group, is acylated by treatment with an organic sulfonyl chloride, such as a lower alkanesulfonyl chloride (e.g., mesyl chloride) or tosyl chloride, to yield the corresponding 21-sulfonic acid ester (Compounds O and P), which are new compounds of this invention.

Compounds 0 and P are then converted to their corresponding 21-iodo derivatives (Compounds Q and R, respectively) by treatment with an alkali metal iodide (e.g., sodium iodide), preferably at an elevated temperature. Compounds Q and R are new compounds of this invention.

Compounds Q and R are then reduced, as by treatment with sodium bisulfite, to yield the final products of this invention which are unsubstituted in the 21-position (Compounds S and T). If a 3,8,15ot-dihydroxy or 3f3,15a-diacyloxy derivative is initially formed it may be oxidized to the corresponding 3,15-diketo derivative (after saponification of the 3- and 15-ester groups, if present) to yield the final 3,15-diketo pregnene compounds of this invention.

Other novel final products of this invention may be prepared according to the processes of this invention, employing the novel starting materials, Compounds I, thereof. These processes may be represented by the following equations, wherein Y, R, R and R are the same or different and represent hydrogen, lower 'alkyl, acyl and together with the oxygen atom to which they are joined may represent 0x0 (0 XXXIIa. R=CHsCO XXXIIl) R H XXXIIo YOzROzO:

XXXIG YIRICHSCO XXXII) YIR: XXXIO YOIOI; RZCHsCO OIRII RII H The 3,15-diester of sulfurenic acid (Compounds I) is first converted to a corresponding diester of A -eburicene- 21-oic acid (Compounds B). This may be accomplished by the hydrogenation of the 3,15-diester in the presence of a hydrogenation catalyst, for example, palladium on charcoal, whereby Compounds B are obtained directly. Alternatively, Compounds B" may be produced by first methylating as by reacting with diazomethane the 3,15- diacetate esters (Compounds 1) in ether to produce the methylated 3,15-diacetate ester of sulfurenic acid. The methylated diacetate ester (Compounds I) is then treated with hydrogen in the presence of a hydrogenation catalyst to produce the A -eburicene-diesters (Compounds B").

Compounds B" are then oxidized as by treatment with an oxidizing agent, for example, chromic acid in an acetic acid medium to produce the A -eburicene-7,11- diones (Compounds C"). To obtain the 21-oic acids of Compounds C (wherein R is hydrogen), Compounds C" may be demethylated as by treatment with a lithium halide in a basic medium, such as collidine, at elevated temperatures.

Compounds C are then reduced as by treatment with zinc in glacial acetic acid preferably at elevated temperatures to produce the eburicane-7,11-diones (Compounds D). In order to obtain the 21-oic acids of Compounds D" (wherein R is hydrogen), Compounds D are demethylated as by treatment with a lithium halide in a basic medium, such as collidine at elevated temperatures.

Compounds D are then converted to the ll-ketoeburicane (Compounds F) by treatment first with an alkylene-dithiol, e.g., ethane-dithiol, in the presence of a Lewis acid, such as, borontrifiuoride etherate to produce the dit-hioethylene ketals (Compounds E"), which are new compounds of this invention. Compounds E may .then be treated at elevated temperatures with a sponge nickel catalyst in an organic solvent (e.g., ethanol), to produce Compounds F", which are also new compounds of this invention.

Alternatively, Compounds F" may be obtained by treating Compounds D" with hydrazine and a base, such as potassium hydroxide, at elevated temperature. In addition to the reduction of the 7-keto group, there occurs hydrolysis of the ester groups at C C and C and the latter are reformed by treatment first with an acylating' agent (i.e., acid anhydride or acyl chloride) in the presence of a base (e.g., pyridine) followed by treatment with a methylating agent (e.g., ethereal diazomethane), to produce Compounds F directly.

In order to obtain the 21-oic acids of Compounds F" (wherein R=hydrogen) Compounds F" are demethylated as by treatment with a lithium halide in a basic medium, such as collidine, at elevated temperatures. The eburicane 21-oic acids Compounds F" (wherein R is hydrogen), are then treated with an acid halide (e.g., thionyl chloride or thionyl bromide) to produce the eburicane-21-oyl chlorides (Compounds G"). These are also new compounds of this invention.

Compounds G" are then reduced as by treatment with hydrogen in the presence of a palladium catalyst at an elevated temperature to yield the eburicane-2l-al-11ones' (Compounds H), which are new compounds of this invention.

Compounds H" are then treated with a secondary amine, such as pyrrolidine, at an elevated temperature, with or without a strong acid, such as p-toluenesulfonic acid, to produce the 21-(N-substituted)-A -eburicene-1lones (Compounds J"), such as 21-(N-pyrrolidyl)-A eburicene-ll-one, which are also new compounds of this invention. Similarly, additional 21-(N-substituted)-A eburicenes (Compounds J") may be obtained by substituting other secondary amines for the pyrrolidine employed above. Examples of such secondary amines are morpholine and piperidine, which when employed in the practice of this invention, yield respectively 21-(N- morpholyl)-A -eburicene-11-one, and 21- (N-piperidyl)- A -eburicene-1 l-one (Compounds I") which are also new compounds of this invention.

Compounds I" may then be ozonized with an excess of ozone at reduced temperatures. The ozonide formed is then reduced, as by treatment with zinc and acetic acid, to yield the ZI-nOr-eburicane-l1,20-diones (Compounds K"), which are also new compounds of this invention.

treating Compounds K" with a peracid, such as trifluoroperacetic acid which yields the 3,15-diacetate-17(4,5- dimethylhexanoate) of 4,4,l4-trimethyl androstane (Compounds L), which are new compounds of this invention.

When in the practice of this invention, the diacyl ester compounds (Compounds L") are obtained, the diester can be saponified in the usual manner, as by treatment with a base, such as potassium hydroxide, to yield the corresponding free dihydroxy derivative and the free dihydroxy compounds oxidized to the corresponding keto derivative in the usual manner as by treatment with chromium trioxide to yield Compounds M, which are new final products of this invention. Additionally, subsequent reduction of the final compounds, such as by treatment with lithium borohydride, results in the production of additional new final products of this invention (Compounds M).

It has also been found in the practice of this invention that when the starting materials thereof, i.e., Compounds I" possess a 15-keto substituted (e.g., wherein YO is oxo [O=]), that substituent is maintained throughout the process thus yielding the 3-substituted 15-k-eto compounds of this invention.

In addition to the foregoing process, further steps may be employed to obtain further products of this invention. The basic starting material is the same employed in the hereinbefore disclosed process, which starting material is the source of the reactant employed in obtaining the additional products of this invention. The following equations represent the process whereby additional products are obtained, wherein Y, R, R and R" are as hereinbefore defined:

R CHaCO XLIg Y=R:R'=R"=H In the first step of the subsequent process, Compounds I, obtained as described hereinbefore, are oxidized, as with chromic acid in an acid medium, to yield the A -lanostene- 7,11,24-triones (Compounds 0'') directly.

Compounds 0" are treated with a reducing agent, such .as zinc and acetic acid, to yield the lanostane-7,11,24- triones (Compounds P), which are new compounds of this invention.

Compounds P" are then reacted with an alkylene dithiol, such as ethanedithiol, in the presence of a Lewis acid, such as boron trifiuoride-etherate catalyst under mild conditions, to yield the dithioethylene ketals (Compounds R") which are new compounds of this invention. Compounds R" are then desulfurized as by heating at elevated temperatures in an organic solvent, in the presence of a nickel catalyst, thus yielding the lanostane-7, ll-diones (Compounds T) which are new compounds of this invention.

Compounds T" may then be processed according to the steps set forth hereinbefore in the treatment of Compounds E" through M", in order to obtain the final derivatives of Compounds R", which are Compounds V" and are also new products of this invention.

Alternatively, Compounds P" may be treated with an alkylene dithiol in the presence of a boron trifluorideor a MN OR etherate over an extended period of time at room temperature to yield the bis-dithioethylene ketal (Compounds Q) which are new compounds of this invention. Refluxing the bis-dithiolethylene ketals (Compounds Q") in an organic solvent in the presence of a nickel catalyst yields the lanostane-ll-ones (Compounds S").

Compounds S" may also be obtained directly by treating Compounds P", at an elevated temperature, with a base, such as potassium hydroxide, and a hydrazine hydrate, and reacetylating the compound formed, as by treatment with acetic anhydride in a tertiary base, and then remethylating, as by treatment with ethereal diazomethane, to obtain Compounds S" directly.

To obtain additional final products of this invention, Compounds S" are treated according to the procedures set forth hereinbefore in the treatment of Compounds F" through M", thus yielding the ll-keto androstane derivatives (Compounds U) which are also new final products of this invention.

An additional method of producing the final products of this invention involves the employment of the derivatives of Compounds B", as starting material. The different steps of the process and the compounds obtained therefrom can be represented by the following equations, wherein Y, R, R and R" are as hereinbefore described.

XLVIIa Y' RZCHsCO; Azhalide XLVIII) YO:O:; RICHsCO; A=httlide XLVIIIa YZR CHsCO XLVIIIb Y R H XLVIIIG YO RO O XLVIIItl YOZOZ; RZCHBCO In the first step of the process yielding additional final products of this invention, Compounds B" (wherein R is hydrogen) are treated with a halogenating agent, such as, thionyl chloride, at an elevated temperature to yield diacetyl dihydrosulfurenoyl chloride (Compounds BB).

Compound BB is then treated in accordance with the procedures set forth hereinbefore in the processing of Compounds F through K" to obtain the A -21-noreburicanes (Compounds CC) which are additional new final compounds of this invention.

Still further additional final products of this invention may be obtained by the processing of the derivatives of Compounds F or Compounds S" (wherein R is hydrogen), obtained as set forth hereinbefore. The additional products are obtained by the process represented by the following equations wherein Y, R, R and R" are the same as defined hereinbefore; and R" may be hydrogen or lower alkyl:

In the first step of the process yielding these additional final products, Compounds F" or S" (wherein R is hydrogen), obtained as set forth hereinbefore, are treated with lithium borohydride in tetrahydrofuran to produce the ll-hydroxylanostanes (Compounds DD) which are new compounds of this invention.

Compounds DD are then treated with methanesulfonyl chloride and pyridine in dirnethylformamide to yield the A -Ianostenes (Compounds EE'), which are also new compounds of this invention.

XLIVa YIR CHsCO R":H

ROg M- OR" Y=R=CHsCb rv=crn dimethyl hexanoy hexanoyl) methyl hexanoyl) produce the eburicane-7-ones (Compounds Y), which 65 are new compounds of this invention. Compounds Y may then be demethylated as by treatment with a lithium halide in a basic medium, such as oollidine, at elevated temperatures to produce the eburicane-7-one-21-acids (Compounds X") which are also new compounds of this 70 invention.

To obtain additional final products of this invention, Compounds X" are treated in accordance with the procedures set forth hereinbefore in the processing of pounds X" results in the production of the 7-ketoandr-ostane derivatives (Compounds AA) which are new final products of this invention.

Still other final products of this invention may be obtained by treating Compounds Y in accordance with the procedure set forth hereinbefore'for the processing of Compounds D" through M". Thus, Compounds Y" are first treated with an alkylendithiol in the presence of a Lewis acid to produce the 7-dithioethylene ketals (Compounds Y") which compounds are then desulfurized to produce the 3,15-disubsti-tuted eburicanes (Compounds Y"). Compounds Y" may then be treated in accordance with the procedures set forth hereinbefore for the treatment of Compounds F" through M", thus providing new final products of this inven- Compounds B" through M". Such treatment of Com- 75 tion (Compounds Z").

Compounds EE' are then treated in accordance with the thus yielding as new additional final products of this invenprocedures set forth above for obtaining Compounds 6'' tion the 7,1l-diketo-A -androstenes (Compounds GG) through K", thus yielding the A -21-nor-lanostenes and the 7,11-diketo-androstanes (Compounds HH). (Compounds FF), which are new additional final prodi It is to be noted that when any of the starting materials nets of this invention. 5 or intermediates described herein, possess a IS-keto sub- Still more final products may be obtained from the stituent (i.e., YO=O=), and these compounds are then further processing of Compounds C" and D", (wherein treated in accordance with the procedure set forth here- R' is hydrogen). Instead of further degradation of these inabove, the final products and the intermediates produced compounds as set forth hereinbefore they are treated dithereby will also possess this 15-ketosubstituent (i.e. rectly to obtain new final products of this invention by 10 YO=O). I a f 1 the process set forth in the following equations, wherein Additional final products of this invention may be pre- Y, R, R and R" are as hereinbefore defined: pared *in accordance with the procedures represented by 1 ill Compounds C and D" (wherein R is hydrogen) are i the' following equations, wherein Y, R, R and R" are as processed according to the procedures set forth hereinbet hereinbefore defined, and Z represents hydrogen, hydroxy, fore in the production of Compounds G through M", acyl or halogen.

CHzZ

LXIVC Z OH; Y CHsCO Compounds F obtained as hereinbefore described can first be isomerized to the corresponding 3,15-diacetoxy- 24-hydroxy-A -lanostatriene-Zl-oic acid lactone derivative (Compounds G), by treatment with hydrogen chloride in a solvent (e.g. glacial acetic acid).

The lanostatriene-Zl-oic acid lactones (Compounds F and G) may then be oxidized by treatment with potassium permanganate, and the manganese dioxide formed, reduced as by treatment with sulfur dioxide, to form the A -Sa-andmstene 7,11 dione 175 carboxylates (Compounds H), which are new compounds of this invention.

Compounds iH' are then reduced as by treatment with zinc in glacial acetic acid, preferably at elevated temper atures to yield the 5a-androstane-7,1-1-di0ne-17,B-carboxylates (Compounds J'), which are also new com pounds of this invention.

Compounds 1" are then converted to the 11-keto-5aandrostanes (Compounds L') by treatment first with an alkylenedithiol, such as ethanedithiol, in the presence of a Lewis acid, such as borontrifluoride etherate, to produce the dithioethylene ketals (Compounds K). Compounds K" may then be treated at elevated temperatureswith a sponge nickel catalystin anorganic solvent (e.g. ethanol) to produce Compounds L, which are new compounds of this invention.

Alternatively, compounds L may be obtained by treating Compounds J with hydrazine and a base, such as potassium hydroxide, at elevated temperatures. In addition to the reduction of the 7-keto group, there occurs hydrolysis of the ester groups at C C and C and the latter are reformed by treatment first with an acylating agent such as acid anhydride or acyl chloride, in with a methylating agent (e.g., ethereal diazomethane), to produce Compounds L' directly.

The ll-keto-ja-androstanes (Compounds L') may then be dehydrated and rearranged as by treatment with phosphorus pentachloride at reduced temperature in the absence of light, to yield the 3-alkylene-1l-keto-lS-substituted-A-nor-Sa-androstanes (Compounds M'), which are also new compounds of this invention.

Compounds M' are then treated with ozone and the ozonide formed is reduced, as by treatment with zinc and glacial acetic .acid to yield the 3,11-diketo-15-substituted-A-nor-Srx-androstanes (Compounds N) (wherein R is SocH and R is 0H which are: also new compounds of this invention.

These Compounds N (wherein R' is SooH and R is CH may then be hydrolyzed, as by treatment with alkali such as potassium hydroxide at elevated temperatures, to form the free acid compounds with simultaneous epimerization at the C position, thus yielding Compounds N' (wherein R is 'SfiH and R is H), directly. Alternatively, these free acid compounds may be ment of Compounds N (wherein R is Sal-I and R is CH with cold alkali to produce Compounds N' (wherein R is 5,8H and R is CH followed by treatment with hot alkali to yield Compounds N (wherein 'R is 55H and R is H).

Compounds N' may then be treated with an acid halide, for example, oxyalyl chloride, to obtain the A- nor-5,8-androstane-17fl-carboxylic acid halides (Compounds O'), which are also new compounds of the instant invention.

Compounds are then treated with a methylating agent, for example, ethereal diazomethane to produce 2 1- diazo-20-keto-A-nor-pregnanes (Compounds P) which are new compounds of this invention.

In order to obtain the final products of this invention which are oxygenated in the 21-position (i.e. Z is acyloxy or hydroxy), Compounds P are treated at elevated tem perature with a fatty acid, such as acetic, propionic or butyric acid, to yield the 21-esters of 3,11,20-triketo-15- substituted-A-nor-S S- regnane (Compounds Q') which are also new compounds of this invention. Alternatively, Compounds Q (wherein Z is acyloxy) may be obtained by first treating Compounds P with a hydrohalide, such as hydrochloric acid, to yield the 21-halogenated A-norpregnanes (Compounds Q'), which are also new compounds of this invention, and then acylating the 21- halide A-norpregnanes as by treatment with potassium acetate and potassium iodide to yield the 21-acyloxyA- norpregnanes (Compounds Q). To obtain the 2l1-hydroxy A-norpregnanes, the 2l-acyloxy compounds are treated with a base, such as potassium carbonate. The 21-hydroxy A-norpregnanes are also new compounds of this invention.

Compounds Q are then brominated as by treatment with bromine in an acid medium to yield the ZI-oxygenated 5-bromo-A-nor-pregnanes (Compounds R'), which are also new compounds of this invention. The 21-oxygenated 5-'b=romo-A-n-orpregn anes are then converted to the 21-oxygenated-A-nor-A -pregnenes (Compounds 5') by treatment with a base, such as collidine or lithium halide, e.g., lithium chloride or lithium bromide in dimethylformamide. Compounds 8" are new final products of this invention.

To obtain the tfinal compounds of this invention, which are not oxygenated in the 21-position (i.e., wherein Z is halide or hydrogen), Compounds -P" are first treated with a reducing agent, such as hydriodic acid, to yield the Zl-unsubstituted A-norpregnanes (Compounds Q), which are new compounds of this invention. The 2l-unsubstituted pregnanes are then brominated, as by treatment with bromine in an acid medium, to yield the 21- unsubstituted 5 -bromo-A-norpregnanes (Compounds R'), which are then converted to the ZI-unsubstituted A-nor-A -pregnenes (Compounds 8") by treatment with a base, such as collidine or a lithium halide, such as lithium chloride, in dimethylformamide. These are also new compounds of the instant invention.

The sfinal products of this invention which are halogenated in the ll-position (i.e., wherein Z may be chlorobromo-fiuoro or iodo) are obtained by first treating, at reduced temperatures, the .Zl-diazoketone (Compounds P) with a hydrogen halide such as hydrogen chloride, to yield the corresponding 2l-ha1o substituted A-norpregnanes (Compounds Q), which are also new compounds of this invention. The 2'1-halo substituted compounds are then brominated as by treatment with bromine in an acid medium, and the resultant S-bromo-Zl-halo-A-norpregnanes (Compounds R') are dehydrobrominated as by treatment wth lithium halide in dimethylformamide to yield the 2l-halo-A-nor-A -pregnenes (Compounds 8), which are new final products of the instant invention.

The new final products of this invention may also be obtained by alternate procedures which may be represented by the following equations, wherein Y, R, R and Z are as hereinbefore defined:

COOR COOR COOR COOR i --OY --OY :Q

Z/II I U!!! LXVIIa RzCHa; Zzhalide; LXVIa RzCHa; zzlmllde;

Y CHsCO :CH; 0 LXVIIb RzH; X=ha11de LXVIb R:H Zzhalide;

YZCHaCO Y=CHaCO LYyVIIc R:CH.-1; Zzlialide; LXYVIe Il -CH3; Z:halide;

(IJOOR (IJOOR -OY --OY 0- 3 WII! VIII LXVIIIa R CHs; Y=CHaCO LXVIIIb R:H; YzCHsCO LXVIIIG RzCHs; YO O:

LXIXIZ R=CHs; Y CHaCO LXIXI) RZH; YICHSCO LXIXC RICHa; YOZO:

LXXa Zzhalide; Y:CHsCO LXXb z halide; YOZO:

COZ

LXXIa Zzhalide; Y=CHaCO LXXIT) z halide; YOZO:

LXXIIa Y=CHaCO LXXIII) YOzO:

ll. Ll

F III LXXVa Zzhalid (Cl, Br, F,

01 I) Y CHeCO LXXVb Z:CHeCOO;

YICHaCO LXXVO ZzOH; YICHsCO LXXVd ZZH; YzCHsCO LXXVe Z:ha1ide; YO O: LXXVf Z=CH3COO YO:O::

LXXIIIa YzCHaCO LXXIIIb YOzO:

38 In the first step of the alternate procedure which may be employed to obtain the final products of this invention, the 3,11 diketo 1S-substituted-A-norandrostanes (Compounds N) are treated with an enol ester of a carbocylic acid of less than 10 carbon atoms of an aliphatic ketone, such as isopropenyl acetate in the presence of a strong acid, e.g. p-toluenesulfonic acid, to produce the 11 keto lS-substituted-A-nor-N andro- Y stenes, (Compounds T), which are also new compounds of this invention. Compounds T' may then be halogenated, as by treatment with a halogenating agent, such as N-bromoacetamide, N-bromosuccinimide, dibromodimethylhydantoin, bromine, N-chlorosuccinimide or N- iodoacetamide, to yield the 5-halo-3,1l-diketo-lS-substituted-A-nor-SB-androstanes (Compounds U'), which are also new compounds of this invention.

Dehydrohalogenation of Compounds U, as by treatment with lithium bromide in dimethylformamide or collidine, yields a mixture of the unsaturated steroids, A-nor-M-androstenes (Compounds W) and Anor-A androstenes (Compounds V) both of which are new compounds of this invention. The mixture of these compounds may be separated into the individual components (Compounds V' and Compounds W) by fractional crystallization, in order to further process the individual compounds to obtain the additional products of this invention. In addition to the foregoing, an alternate method may be employed to obtain Compounds W, which first entails treating Compounds N' with bromine in an acid medium, such as glacial acetic acid, to obtain the 5a-halo-A-nor-5a-androstanes (Compounds Z) which are new compounds of this invention. Compounds Z' may then be'dehydrohalogenated as by treatment with lithium bromide in dimethylformamide or collidine to yield the A-nor-A -androstenes (Compounds W)v Compounds W and V may then be converted to the final A-nor-pregnene derivatives of this invention by an identical series of steps. If a compound W is em ployed, the final product and all the intermediates thereof contain a double bond in the 5,6-position. If a compound V is employed, the final products and all intermediates contain a double bond in the 1,2-position.

In the first of this series of steps, Compounds W and V (R=H) are treated with an acid halide, for example, oxalyl chloride, to obtain the corresponding A-nor-M-androstene-l7fl-carboxylic acid halides (Compounds AA) and the A-nor-d -an-drostene-17B-carboxylic acid halides (Compounds DD), respectively. These are also new compounds of this invention, These compounds are then converted to their respective diazoketone-A-nor-A -pregnenes (Compounds BB) and diazoketone A nor-d -pregnenes (Compounds EE) derivatives as by treatment with an ethereal solution of diazomethane.

Compounds BB and Compoupnds EE are then converted to the 2l-substituted final products of this invention as set forth hereinbefore in the treatment of Compounds P' to produce Compounds 5" and Compounds FF, which are new final products of this invention. Thus, treatment of Compounds EE with a fatty acid, such as acetic, propionic or butyric acid yields the 21-esters of the A-nor-o -pregnenes (Compounds FF), which are new final products of this invention. Treating Compounds EE' with a hydrohalide, such as hydrogen chloride, yields final products of this invention which are 2l-halo substituted and are also new final products of this invention. The ZI-unsubstituted derivatives are obtained by treating Compounds BB' and EE with hydroiodic acid, thus yielding the A-nor-A -pregnenes (Compounds 8) and the A-nor-Npregnenes (Compounds FF'), which are new compounds of the instant invention.

In addition, the 21-unsubstituted (i.e., Z is H), saturated final products of this invention may be obtained by an alternate procedure, which may be represented by the following equations, wherein Y, R, R and Z are as hereinbefore defined:

COOR COZ In the first step of this alternate process, Compounds M (wherein R is H) are treated with an acid halide, for example, oxalyl chloride, to produce the 3-alkylene-15- acyloxy-A-nor-Sa-andrOstane-l7/3-carboxylic acid halides (Compounds CC'), which are also new compounds of this invention. Compounds CC are then treated with an ethereal solution of dimethyl cadmium to yield the 3- alkylene-1S-acyloxy-A-nor-Sa-pregnane-11,20 diketones (Compounds GG) which are also new compounds of this invention. Compounds 66 are then ozonized to yield the A-nor-a-pregnane-15-acyloxy-3,11,20-triketones (Compounds HH), which are also new compounds of this invention. Compounds HH' may then be treated with a base, such as sodium hydroxide to yield the A-nor- Sfi-pregnane substituted 3,11,20 triketones (Compounds Q') (wherein Z is H), which are new compounds of this invention.

Addition-ally, further new products of this invention may be obtained by alternate procedures, employing the same or derivative starting material therefor. The starting material employed in obtaining the further products of this invention is derived from the acid starting material disclosed hereinbefore. The derivative employed in this alternate process is reacted according to the equations set forth below.

The following equations represent additional alternative processes which may be employed in the practice of the invention to yield further new products, wherein Y, R, R and Z are as hereinbefore defined:

OOOR

l Boga,

all, ll 3 (IJOOR (IIOOR CIHzZ LXXXIId Z=H; YzCHaCO LXYXXIIC zzhalide; 

11. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS OF THE FORMULAE 